Abstract
A novel Ras-farnesyltransferase inhibitor designated TAN-1813 was isolated from the culture broth of a fungus strain, FL-41510, isolated as a plant endophyte. The producer was taxonomically characterized as Phoma sp. FL-41510. TAN-1813 inhibited rat brain farnesyltransferase and geranylgeranyltransferase I activity with IC50 values of 23 μg/ml and 47 μg/ml, respectively. TAN-1813 showed mixed-type inhibition with respect to farnesylpyrophosphate and noncompetitive inhibition with respect to a K-Ras C-terminal pep tide. It also inhibited the in situ farnesylation of cellular Ras proteins in a K-ras transformant (NIH3T3/K-ras) of mouse embryonic fibroblast cell line NIH3T3.
TAN-1813 inhibited the proliferation of various human cancer cells, some of which harbor activated ras alleles, with IC50 values of 15-110ng/ml as well as that of NIH3T3 and NIH3T3/K-ras cells with IC50s of 540 and 310ng/ml, respectively. Flow cytometric analysis indicated that TAN-1813 arrests NIH3T3/K-ras cells at both Gl and G2/M phases of the cell cycle. In addition, TAN-1813 was found to induce morphological reversion of NIH3T3/K-ras cells from the transformed phenotype. Antitumor activity of TAN-1813 against human fibrosarcoma HT-1080 and NIH3T3/K-ras tumors in nude mice was also verified.
